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. 2023 Nov 7;24(22):16027.
doi: 10.3390/ijms242216027.

Data Mining Suggests That CXCL14 Gene Silencing in Colon Cancer Is Due to Promoter Methylation

Yanjing Wang  1 , Siyi Wang  1 , Yuchen Niu  1 , Buyong Ma  1 , Jingjing Li  1
Affiliations

Data Mining Suggests That CXCL14 Gene Silencing in Colon Cancer Is Due to Promoter Methylation

Yanjing Wang et al. Int J Mol Sci. .

Abstract

CXCL14 is one of the most evolutionarily conserved members of the chemokine family and is constitutionally expressed in multiple organs, suggesting that it is involved in the homeostasis maintenance of the system. CXCL14 is highly expressed in colon epithelial cells and shows obvious gene silencing in clinical colon cancer samples, suggesting that its silencing is related to the immune escape of cancer cells. In this paper, we analyzed the expression profiles of multiple human clinical colon cancer datasets and mouse colon cancer models to reveal the variation trend of CXCL14 expression during colitis, colon polyps, primary colon cancer, and liver metastases. The relationship between CXCL14 gene silencing and promoter hypermethylation was revealed through the colorectal carcinoma methylation database. The results suggest that CXCL14 is a tumor suppressor gene in colorectal carcinoma which is activated first and then silenced during the process of tumor occurrence and deterioration. Promoter hypermethylation is the main cause of CXCL14 silencing. The methylation level of CXCL14 is correlated with the anatomic site of tumor occurrence, positively correlated with patient age, and associated with prognosis. Reversing the hypermethylation of CXCL14 may be an epigenetic therapy for colon cancer.

Keywords: CXCL14; DNA methylation; colorectal cancer; gene silence; metastasis.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
CXCL14 was downregulated in clinical colorectal carcinoma. (A) CXCL14 expression level in 259 samples of different stages of tumorigenesis and 10 colorectal carcinoma cell lines. (B) CXCL14 expression level of E-GEOD-4183 dataset, including 15 patients with CRC, 15 with adenoma, 15 with IBD, and 8 healthy normal controls. (C) CXCL14 expression profile in E-GEOD-23878 dataset with 35 CRC and 24 normal samples. (D) Overview of CXCL14 expression in E-GEOD-49355 dataset of normal colon, primary tumor, and liver metastasis samples of 13 patients. (E) Line chart of CXCL14 expression of different sample types. (F,G) Paired comparisons of normal primary tumor and primary metastasis tumor. The red lines highlight the samples that go against the gene silence trend. (H) Expression profile in the mouse primary colon cancer model. (I) Expression profile in the AOM/DSS-induced CRC model. *: p < 0.05, **: p < 0.01, ***: p < 0.001. ns: not significant.
Figure 2
Figure 2
Survival curves of colon cancer with different CXCL14 expression levels. (A) Kaplan–Meier survival curve of TCGA database Colon Adenocarcinoma (TCGA-COAD). (B) Survival curve of the Gepia COAD dataset. (C) Correlation of overall survival (OS) of the Sidra-LUMC AC-ICAM dataset.
Figure 3
Figure 3
CXCL14 promoter was hypermethylated in the primary tumor. (A) Tumor sample and normal control of the TCGA dataset; 5 mC was sequenced by bisulfite sequencing. (B) Probe number in (A). (C–E) Paired samples of the primary tumor and normal control were compared in the #6~8 locus. (F–H) The correlation between RNA expression and methylation level was assayed by a correlation study. **: p < 0.01, ***: p < 0.001, ****: p <0.0001. ns: not significant.
Figure 4
Figure 4
Methylation of the CXCL14 promoter was correlated with the anatomic neoplasm subdivision of the primary tumor and age at diagnosis. (A) The CXCL14 promoter methylation level in the different anatomic subdivisions of the colon. (B) CXCL14 mRNA level in different anatomic subdivisions of the colon. (C) The correlation analysis of the CXCL14 methylation level of normal colon tissue and donor’s age. (D) Tumor samples were separated into hyper- and hypo-methylation groups by 0.1 of β-value. (E) The group of hypermethylation showed a mild correlation between β-value and age at diagnosis. (F) There is no correlation in the group of hypomethylation. *** p < 0.001. ns: not significant.
Figure 5
Figure 5
Methylation of the CXCL14 promoter is associated with prognosis. (A–H) Kaplan–Meier survival curve of higher and lower CXCL14 promoter methylation group for different probes in the TCGA colorectal database. (I–K) Kaplan–Meier survival curve examination of overall survival in subjects with high and low methylation levels in the hypermethylation group, as mentioned in Figure 4D.
Figure 6
Figure 6
CXCL14 promoter methylation is negatively correlated with transcription level. (A) HT-29 and (B) HCT116 were treated with DAC with gradient concentration and CXCL14 silencing was reversed. (C) CXCL14 transcription in HT29 was activated by DAC treatment and decreased after drug withdrawal. (D) Plasmids containing different lengths of truncated CXCL14 promoter were evaluated by a luciferase assay. (E) Methylation of the −170~100 region of CXCL14 promoter by M.SssI treatment decreases CXCL14 expression. *: p < 0.05, **: p < 0.01, ***: p < 0.001.
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